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  • 1
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    Online Resource
    IMMU-12. TUMOR CELL IDO ENHANCES IMMUNE SUPPRESSION AND DECREASES SURVIVAL INDEPENDENT OF TRYPTOPHAN METABOLISM IN GLIOBLASTOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi94-vi94
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi94-vi94
    Abstract: Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is an immune checkpoint that’s characterized as a potent immunosuppressive mediator through its ability to metabolize tryptophan and wild-type IDH patient-resected glioblastoma (GBM) expresses IDO in ≥ 95% of cases. Recent findings from our group led us to investigate the alternative hypothesis that IDO possesses immunosuppressive effects that are independent of its associated metabolic activity. METHODS Murine GBM cell lines that overexpress either wild-type or enzyme-null IDO were created for in vivo characterization of IDO enzyme-independent immunosuppressive function. Microarray was conducted to identify human IDO expression-correlated genes, which were further investigated in human GBM cell lines, patient GBM tissues and plasma, as well as the TCGA database. Ex vivo cell co-culture assays and syngeneic mouse orthotopic GBM models were employed to study immunosuppressive mechanisms. RESULTS Here, we demonstrate that non-enzymic IDO activity decreases survival in experimental animals and increases the expression of immunosuppressive complement factor H (CFH) in human GBM. CFH mRNA levels positively correlate with those of IDO and many other immunosuppressive genes in patient resected GBM and can be applied as a prognostic marker in both lower grade gliomas and GBM. Similar to IDO, the increased expression of CFH in patient-resected glioma was positively correlated with an increased signature for regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs). High expression of CFH in tumor cells increases intratumoral Tregs levels and decreases overall survival in mice with GBM, while inducing tumor associated macrophage cell differentiation. CONCLUSIONS Here, we demonstrated that glioblastoma (GBM) cell IDO promotes the accumulation of intratumoral FoxP3+ regulatory T cells (Tregs) and tumor progression while decreasing overall survival - independent of IDO enzyme activity. Our study reveals a targetable non-metabolic IDO-dependent mechanism for future therapeutic intervention in patients with GBM.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.371
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 2
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    Online Resource
    Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 23 ( 2021-12-01), p. 6514-6528
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 23 ( 2021-12-01), p. 6514-6528
    Abstract: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to date. More than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative hypothesis that IDO suppresses the anti-GBM immune response independent of its association with Trp metabolism. Experimental Design: IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO enzyme–null cDNA were created and validated in vitro and in vivo. Microarray analysis was conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell lines, patient GBM and plasma, and The Cancer Genome Atlas (TCGA) database. Ex vivo cell coculture assays, syngeneic and humanized mouse GBM models, were used to test the alternative hypothesis. Results: Nonenzymic tumor cell IDO activity decreased the survival of experimental animals and increased the expression of complement factor H (CFH) and its isoform, factor H like protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression independent of Trp metabolism. Increased intratumoral CFH and FHL-1 levels were associated with poorer survival among patients with glioma. Similar to IDO effects, GBM cell FHL-1 expression increased intratumoral regulatory T cells (Treg) and myeloid-derived suppressor cells while it decreased overall survival in mice with GBM. Conclusions: Our study reveals a nonmetabolic IDO-mediated enhancement of CFH expression and provides a new therapeutic target for patients with GBM.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-1392
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    A systematic review of pharmacologic treatment efficacy for depression in older patients with cancer
    Elsevier BV ; 2022
    In:  Brain, Behavior, & Immunity - Health Vol. 21 ( 2022-05), p. 100449-
    Details
    In: Brain, Behavior, & Immunity - Health, Elsevier BV, Vol. 21 ( 2022-05), p. 100449-
    Type of Medium: Online Resource
    ISSN: 2666-3546
    URL: Article
    DOI: 10.1016/j.bbih.2022.100449
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 3062237-2
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  • 4
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    IMMU-06. REDUCTION OF CD4+ T CELLS NEGATIVELY AFFECTS SURVIVAL IN OLD BUT NOT YOUNG MICE WITH GLIOBLASTOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii132-vii132
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii132-vii132
    Abstract: Previous work indicates poorer survival outcomes for older glioblastoma (GBM) patients ≥ 65 years of age as compared to younger patients & lt; 65 years of age. The cellular mechanisms associated with this age-dependent survival difference remain elusive. Here we evaluated the overall survival of young and old immunocompetent mice with intracranial brain tumors that were depleted for specific immune cell populations. METHODS Young 6-8 weeks of age vs old 80+ weeks of age C57BL/6 mice were treated for up to 3 weeks with either IgG isotype control antibodies or with depleting antibodies against murine CD4, CD8, or NK1.1, beginning at 3 days prior to- and every 3 days post-intracranial injection of the mouse brain tumor cell lines, GL261 or CT-2A. Overall survival was compared between groups. Additionally, absolute peripheral blood mononuclear cell (PBMC) counts for CD3+ T cells, CD4+ T cells, and CD8+ T cells were analyzed between aneurysm control- and GBM-patients. RESULTS Older adult mice, but not younger mice, with either intracranial GL261 or CT-2A cell-based brain tumors have a significantly decreased overall survival when depleted for CD4+ T cells as compared to the IgG control-treated group, as well as groups depleted for CD8+ T- or NK-cells (P & lt; 0.05). Coincidently, older GBM patients have fewer CD4+ T cells as compared to younger GBM patient counterparts (P & lt; 0.05). CONCLUSIONS The data suggest that the levels of CD4+ T cells play more important roles in the survival of old subjects with GBM than in the younger subjects. A mechanistic understanding for this CD4+ T cell-dependent survival benefit is ongoing.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.504
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 5
    Online Resource
    Online Resource
    EPID-08. AGE-STRATIFIED SURVIVAL ANALYSES OF PHARMACOLOGICAL TREATMENTS IN PATIENTS WITH GLIOBLASTOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii111-vii111
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii111-vii111
    Abstract: Glioblastoma is the most common primary malignant brain tumor in adults. Age is a prognostic factor for grade IV glioma (GIV) survival, where older adults 65 and older, tend to have quicker mortality compared to adults 18-64. This may be due to intrinsic aspects of the aged host, including age-dependent changes to the brain and immune systems. We studied pharmacologic management of GIV patients treated with medications affecting the brain, immune, and other systems for associations with age and survival. Electronic records for 1,208 GIV patients were collected at a single institution from 1/1/2000 to 9/8/2021 and used to construct a multivariable time-dependent cox model that examined intra-cohort hazards associated with 14 different categories of outpatient medications. Date of diagnosis was identified as the start-time and subject death was used to define the event-time. Patients who were alive or lost to follow-up were censored to last recorded date. Survival time was calculated as the difference between diagnosis date and event time or censorship. For positive control, we confirmed that younger and older patients experienced an improved hazard with temozolomide. Strikingly, younger, but not older patients, experienced increased hazard with a steroid prescription (1.46 [1.12,1.90], **). In contrast, older, but not younger patients experienced improvements in hazard with prescription of neurological medications including benzodiazepines (0.47 [0.27, 0.80] **) and anti-convulsants (0.28 [0.08, 0.90] *), in addition to heart failure treatments including angiotensin II inhibitors (0.48 [0.27, 0.85] *) and diuretics (0.30 [0.15, 0.87] *). Patients prescribed antidepressants didn’t show improved hazard across younger and older GIV patients, which consistent with our previously published work. These data indicate novel associative benefits due to prescription of select pharmacologic agents that vary with patient age. This work may be used to better understand therapeutic approaches that selectively benefit younger vs. older adults with GIV.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.418
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 6
    Online Resource
    Online Resource
    CNSC-27. AN IDO-PROTAC HIGHLIGHTS A NOVEL TRYPTOPHAN METABOLISM- INDEPENDENT ROLE FOR IMMUNOSUPPRESSIVE IDO IN HUMAN GLIOBLASTOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii28-vii28
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii28-vii28
    Abstract: Indoleamine 2,3-dioxygenase 1 (IDO) is an immunosuppressive enzyme that catabolizes the essential amino acid, tryptophan (Trp), into the metabolite, kynurenine. IDO is expressed in & gt;90% of patient resected GBM. IDO suppresses the anti-brain tumor immune response, in-part, through non-metabolic activities. To determine how IDO non-metabolically suppresses the anti-GBM immune response, IDO-protein degrader (IDO-proteolysis targeting chimera; IDO-PROTAC) effects were studied in multiple human models of GBM. METHODS The IDO-expressing GBM cell lines, U87, U138, as well as the patient derived xenograft (PDX) line, GBM43, were treated with either IDO-PROTAC, mutant PROTAC, IDO enzyme inhibitor, or IDO siRNA, followed by RNA-seq analysis and/or mass spectrometry with quantitative proteomics using tandem mass tag (TMT) labelling. RESULTS Transcriptomic analysis revealed differentially expressed genes that were commonly regulated after treatment with the IDO-PROTAC as compared to treatment with the mutant PROTAC or IDO enzyme inhibitor groups in U87, U138, and GBM43 cells. Mass spectrometry analysis found 34 unique proteins that were differentially expressed inside of human GBM cells, with an additional 20 unique proteins that were identified in the supernatant of cultured human GBM cells after IDO-PROTAC treatment. Meta-analysis of the transcriptomic and proteomic analyses identified a novel factor that was unique to IDO-PROTAC treatment. GO terms that were enriched after IDO-PROTAC treatment identified nucleoside kinase activity as well as metallocarboxypeptidase activity. CONCLUSIONS This study discovered multiple new targets and pathways that immunosuppressive IDO regulates through a non-metabolic function. Functional analyses that validate the newly-discovered IDO-dependent, IDO-enzyme independent factors, are ongoing.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.108
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    Online Resource
    Advanced age in humans and mouse models of glioblastoma show decreased survival from extratumoral influence
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research ( 2023-09-19)
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), ( 2023-09-19)
    Abstract: Purpose: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68-70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here we studied intratumoral and extratumoral relationships between adult GBM patients and mice with brain tumors across the lifespan. Experimental Design: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas (TCGA) were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. Additionally, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. Results: Human GBM patients ≥65 years of age had a significantly decreased survival compared to their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older GBM patients, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. Conclusions: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0834
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 8
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    Online Resource
    TMIC-15. AGE-RELATED MARKERS FOR SENESCENCE INCREASE IN THE OLDER ADULT EXTRATUMORAL MOUSE BRAIN DUE TO GLIOBLASTOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii274-vii274
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii274-vii274
    Abstract: The median age of onset for glioblastoma (GBM; IDHwt) is 68-70 years. Age is a strong prognostic factor for GBM patient outcomes such that overall survival in older adults is less than their younger counterparts – even after adjustment for MGMT promoter methylation status. Aging is associated with increased levels of senescence in the brain. Several age-related neurological disorders have been shown to improve with senolytic treatments. Here, we explored the effects and therapeutic neutralization of syngeneic brain tumors on increasing senescence levels in the extratumoral brain (ie. outside of the brain tumor) of young and old mice. METHODS General RNA-sequencing, as well as single-cell (sc) RNA-sequencing was performed on extratumoral tissue from young (8-12 weeks) and older adult (80-90 weeks) C57BL/6 mice with or without GL261 and key markers were validated with RT-PCR. The combined effects of the senolytics, dasatinib and quercetin, with radiation, anti-PD-1 mAb, and IDO enzyme inhibitor treatment, was also investigated. RESULTS General- and sc-RNA sequencing revealed a distinct gene expression profile in the extratumoral brain of older mice with syngeneic GL261 as compared to all other groups. RT-PCR results confirmed that the brain tumor increased gene expression for senescence levels, p53, and NFkB signaling in the older adult extratumoral brain. Expression of the senescence marker p16INK4A was primarily localized to oligodendrocyte progenitor cells in the older adult brain. The combinatorial treatment of senolytics with RT, anti-PD-1 mAb, and IDO enzyme inhibitor led to a synergistic survival benefit in older adult mice with GL261 as compared to the treatment with senolytics, or immunotherapy, alone. CONCLUSIONS The data suggest that the extratumoral brain may be responsible in-part for the poorer outcomes of older adults with GBM and that treatment approaches that target senescent cells may provide clinical benefit.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.1059
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
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    Online Resource
    EPID-09. AGE-STRATIFIED SURVIVAL ANALYSES OF CO-MORBIDITIES IN PATIENTS WITH GRADE IV GLIOMAS
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii111-vii111
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii111-vii111
    Abstract: Glioblastomas are the most common primary malignant brain tumor in adults. Subject age is a strong prognostic factor for survival. We performed a co-morbidity analysis of younger vs. older (greater than 65 years) adults with grade IV gliomas (GIV) to understand inherent differences that vary with subject age. Electronic health records for 1,208 GIV patients were collected at a single center between 1/1/2000 and 9/8/2021 and used to construct a multivariable time-dependent cox model that examined intra-cohort hazards associated with 33 measures of co-morbidity and tumor related symptoms. The date of GIV diagnosis was identified as the start time, and subject death was used to define event time. Patients that were alive or lost to follow-up were censored at the last recorded date. Survival time was calculated as the difference between diagnosis date and event time or censorship. GIV was stratified by IDH and MGMT promoter methylation status when available. Younger patients experienced a greater hazard with: limitations to movement (1.88 [1.46, 2.43] ****), gait (1.72 [1.17, 2.52] **), weakness (1.96 [1.26, 3.06] **), seizures (1.28 [1.04, 1.58] *), epilepsy (1.47 [1.09, 1.99] *), and anxiety disorders (2.37 [1.44, 3.92] , **). Older GIV patients experienced an increased hazard with: confusion and altered mental status (4.3 [2.08, 8.89], ****). Both age groups experienced increases with eye/visual systems and plegia. These data indicate novel comorbid enrichments varying by subject age that, from a mechanistic perspective, may be used to better understand why older adults with GIV survive significantly less than younger counterparts.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.419
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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